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human intestinal organoid

Emily C Moorefield, R Eric Blue, Nancy L Quinney, Martina Gentzsch, Shengli Ding
BACKGROUND: Conditional reprogramming has enabled the development of long-lived, normal epithelial cell lines from mice and humans by in vitro culture with ROCK inhibitor on a feeder layer. We applied this technology to mouse small intestine to create 2D mouse intestinal epithelial monolayers (IEC monolayers) from genetic mouse models for functional analysis. RESULTS: IEC monolayers form epithelial colonies that proliferate on a feeder cell layer and are able to maintain their genotype over long-term passage...
August 15, 2018: BMC Cell Biology
Anna L Means, Tanner J Freeman, Jing Zhu, Luke G Woodbury, Paula Marincola-Smith, Chao Wu, Anne R Meyer, Connie J Weaver, Chandrasekhar Padmanabhan, Hanbing An, Jinghuan Zi, Bronson C Wessinger, Rupesh Chaturvedi, Tasia D Brown, Natasha G Deane, Robert J Coffey, Keith T Wilson, J Joshua Smith, Charles L Sawyers, James R Goldenring, Sergey V Novitskiy, M Kay Washington, Chanjuan Shi, R Daniel Beauchamp
Background & Aims: Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells. Methods: The Smad4 gene was deleted specifically in adult murine intestinal epithelium...
2018: Cellular and Molecular Gastroenterology and Hepatology
Wen Dang, Lei Xu, Buyun Ma, Sunrui Chen, Yuebang Yin, Kyeong-Ok Chang, Maikel P Peppelenbosch, Qiuwei Pan
Norovirus is the main cause of viral gastroenteritis worldwide. Although norovirus gastroenteritis is self-limiting in immunocompetent individuals, chronic infections with debilitating and life-threatening complications occur in immunocompromised patients. Nitazoxanide (NTZ) has been empirically used in the clinic and demonstrated effectiveness against norovirus gastroenteritis. In this study we aimed at uncovering the antiviral potential and mechanisms of NTZ and its active metabolite, tizoxanide (TIZ) using a human norovirus (HuNV) replicon...
August 13, 2018: Antimicrobial Agents and Chemotherapy
Kwang Bo Jung, Hana Lee, Ye Seul Son, Mi-Ok Lee, Young-Dae Kim, Soo Jin Oh, Ohman Kwon, Sunwha Cho, Hyun-Soo Cho, Dae-Soo Kim, Jung-Hwa Oh, Matthias Zilbauer, Jeong-Ki Min, Cho-Rok Jung, Janghwan Kim, Mi-Young Son
Human pluripotent stem cell (hPSC)-derived intestinal organoids (hIOs) form 3D structures organized into crypt and villus domains, making them an excellent in vitro model system for studying human intestinal development and disease. However, hPSC-derived hIOs still require in vivo maturation to fully recapitulate adult intestine, with the mechanism of maturation remaining elusive. Here, we show that the co-culture with human T lymphocytes induce the in vitro maturation of hIOs, and identify STAT3-activating interleukin-2 (IL-2) as the major factor inducing maturation...
August 2, 2018: Nature Communications
Alexander R Cortez, Holly M Poling, Nicole E Brown, Akaljot Singh, Maxime M Mahe, Michael A Helmrath
BACKGROUND: We previously described the development of human intestinal organoids from pluripotent stem cells, as well as their in vivo maturation when transplanted into the mouse kidney capsule. While sufficient for certain aspects of study, this model has limitations. Herein, we describe an alternative model of human intestinal organoids transplantation into the mouse mesentery. We hypothesize that efficient engraftment and marked differentiation of human intestinal organoids will be similar to our kidney model yet in a more anatomically appropriate location allowing for improved in vivo modeling...
July 30, 2018: Surgery
Benjamin Mattes, Yonglong Dang, Gediminas Greicius, Lilian Tamara Kaufmann, Benedikt Prunsche, Jakob Rosenbauer, Johannes Stegmaier, Ralf Mikut, Suat Özbek, Gerd Ulrich Nienhaus, Alexander Schug, David M Virshup, Steffen Scholpp
Signaling filopodia, termed cytonemes, are dynamic actin-based membrane structures that regulate the exchange of signaling molecules and their receptors within tissues. However, how cytoneme formation is regulated remains unclear. Here, we show that Wnt/PCP autocrine signaling controls the emergence of cytonemes, and that cytonemes subsequently control paracrine Wnt/β-catenin signal activation. Upon binding of the Wnt family member Wnt8a, the receptor tyrosine kinase Ror2 gets activated. Ror2/PCP signaling leads to induction of cytonemes, which mediate transport of Wnt8a to neighboring cells...
July 31, 2018: ELife
Joep Beumer, Benedetta Artegiani, Yorick Post, Frank Reimann, Fiona Gribble, Thuc Nghi Nguyen, Hongkui Zeng, Maaike Van den Born, Johan H Van Es, Hans Clevers
Enteroendocrine cells (EECs) control a wide range of physiological processes linked to metabolism1 . We show that EEC hormones are differentially expressed between crypts (for example, Glp1) and villi (for example, secretin). As demonstrated by single-cell mRNA sequencing using murine Lgr5+ cell-derived organoids, BMP4 signals alter the hormone expression profiles of individual EECs to resemble those found in the villus. Accordingly, BMP4 induces hormone switching of EECs migrating up the crypt-villus axis in vivo...
August 2018: Nature Cell Biology
Constanza Alcaino, Kaitlyn R Knutson, Anthony J Treichel, Gulcan Yildiz, Peter R Strege, David R Linden, Joyce H Li, Andrew B Leiter, Joseph H Szurszewski, Gianrico Farrugia, Arthur Beyder
Enterochromaffin (EC) cells constitute the largest population of intestinal epithelial enteroendocrine (EE) cells. EC cells are proposed to be specialized mechanosensory cells that release serotonin in response to epithelial forces, and thereby regulate intestinal fluid secretion. However, it is unknown whether EE and EC cells are directly mechanosensitive, and if so, what the molecular mechanism of their mechanosensitivity is. Consequently, the role of EE and EC cells in gastrointestinal mechanobiology is unclear...
August 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
Cesar A Sommer, Amalia Capilla, Francisco J Molina-Estevez, Andreia Gianotti-Sommer, Nicholas Skvir, Ignacio Caballero, Sanjib Chowdhury, Gustavo Mostoslavsky
Mutations in the gene Adenomatous Polyposis Coli or APC appear in most sporadic cases of colorectal cancer and it is the most frequent mutation causing hereditary Familial Adenomatous Polyposis. The detailed molecular mechanism by which APC mutations predispose to the development of colorectal cancer is not completely understood. This is in part due to the lack of accessibility to appropriate models that recapitulate the early events associated with APC mediated intestinal transformation. We have established a novel platform utilizing human induced Pluripotent Stem cells or iPSC from normal or FAP-specific APC mutant individuals and evaluated the effect of the mutation in the cells before and after differentiation into intestinal organoids...
2018: PloS One
Dennis Schöttelndreier, Katrin Seeger, Guntram A Grassl, Markus R Winny, Robert Lindner, Harald Genth
Toxin-producing strains of Clostridioides difficile and Clostridium perfringens cause infections of the gastrointestinal tract in humans and ruminants, with the toxins being major virulence factors, essential for the infection, and responsible for the onset of severe symptoms. C. difficile toxin A (TcdA) and toxin B (TcdB), and the large cytotoxin (TpeL) from C. perfringens are single chain bacterial protein toxins with an AB-like toxin structure. The C-terminal delivery domain mediates cell entry of the N-terminal glycosyltransferase domain by receptor-mediated endocytosis...
2018: Frontiers in Microbiology
Maria Paz Zafra, Emma M Schatoff, Alyna Katti, Miguel Foronda, Marco Breinig, Anabel Y Schweitzer, Amber Simon, Teng Han, Sukanya Goswami, Emma Montgomery, Jordana Thibado, Edward R Kastenhuber, Francisco J Sánchez-Rivera, Junwei Shi, Christopher R Vakoc, Scott W Lowe, Darjus F Tschaharganeh, Lukas E Dow
CRISPR base editing enables the creation of targeted single-base conversions without generating double-stranded breaks. However, the efficiency of current base editors is very low in many cell types. We reengineered the sequences of BE3, BE4Gam, and xBE3 by codon optimization and incorporation of additional nuclear-localization sequences. Our collection of optimized constitutive and inducible base-editing vector systems dramatically improves the efficiency by which single-nucleotide variants can be created...
July 3, 2018: Nature Biotechnology
Nobel Bhasin, Dereck Alleyne, Olivia A Gray, Sonia S Kupfer
BACKGROUND & AIMS: African Americans have the greatest colorectal cancer (CRC) burden in the United States-inter-ethnic differences in protective effects of vitamin D might contribute to disparities. 1α,25(OH)2 D3 vitamin D (the active form of vitamin D) induces transcription of the uridine phosphorylase gene (UPP1) in colon tissues from European Americans, but to a lesser extent in colon tissues from African Americans. UPP1-knockout mice have increased intestinal concentrations of uridine and dUTP, increased uridine-induced DNA damage, and develop colon tumors...
June 29, 2018: Gastroenterology
Morgane Sébert, Alexandre Denadai-Souza, Muriel Quaranta, Claire Racaud-Sultan, Sophie Chabot, Philippe Lluel, Nicolas Monjotin, Laurent Alric, Guillaume Portier, Sylvain Kirzin, Delphine Bonnet, Audrey Ferrand, Nathalie Vergnolle
BACKGROUND AND PURPOSE: Thrombin is massively released upon tissue damage associated with bleeding or chronic inflammation. The question of the effects of such thrombin on tissue regrowth and repair has been scarcely addressed, and only in cancer cell lines. The purpose of the present study was to determine thrombin's pharmacological effects on human intestinal epithelium growth, proliferation and apoptosis, using 3-dimentional cultures of human colon organoids. EXPERIMENTAL DESIGN: Crypts were isolated from human colonic resections and cultured for 6 days, forming human colon organoids...
June 30, 2018: British Journal of Pharmacology
Ana C F Bolhaqueiro, Richard H van Jaarsveld, Bas Ponsioen, René M Overmeer, Hugo J Snippert, Geert J P L Kops
Examining cell behavior in its correct tissue context is a major challenge in cell biology. The recent development of mammalian stem cell-based organoid cultures offers exciting opportunities to visualize dynamic cellular events in a 3D tissue-like setting. We describe here an approach for live imaging of cell division processes in intestinal organoid cultures derived from human and mouse adult stem cells. These approaches can be extended to the analysis of cellular events in diseased tissue, such as patient-derived tumor organoids...
2018: Methods in Cell Biology
Lisa Luu, Zoe J Matthews, Stuart D Armstrong, Penelope Powell, Tom Wileman, Jonathan M Wastling, Janine L Coombes
Recently, three-dimensional small intestinal organoids (enteroids) have been developed from cultures of intestinal stem cells which differentiate in vitro to generate all the differentiated epithelial cell types associated with the intestine and mimic the structural properties of the intestine observed in vivo. Small-molecule drug treatment can skew organoid epithelial cell differentiation towards particular lineages, and these skewed enteroids may provide useful tools to study specific epithelial cell populations, such as goblet and Paneth cells...
June 28, 2018: Proteomics
Inha Heo, Devanjali Dutta, Deborah A Schaefer, Nino Iakobachvili, Benedetta Artegiani, Norman Sachs, Kim E Boonekamp, Gregory Bowden, Antoni P A Hendrickx, Robert J L Willems, Peter J Peters, Michael W Riggs, Roberta O'Connor, Hans Clevers
Stem-cell-derived organoids recapitulate in vivo physiology of their original tissues, representing valuable systems to model medical disorders such as infectious diseases. Cryptosporidium, a protozoan parasite, is a leading cause of diarrhoea and a major cause of child mortality worldwide. Drug development requires detailed knowledge of the pathophysiology of Cryptosporidium, but experimental approaches have been hindered by the lack of an optimal in vitro culture system. Here, we show that Cryptosporidium can infect epithelial organoids derived from human small intestine and lung...
July 2018: Nature Microbiology
Michael J Workman, John P Gleeson, Elissa J Troisi, Hannah Q Estrada, S Jordan Kerns, Christopher D Hinojosa, Geraldine A Hamilton, Stephan R Targan, Clive N Svendsen, Robert J Barrett
Background and Aims: Human intestinal organoids derived from induced pluripotent stem cells have tremendous potential to elucidate the intestinal epithelium's role in health and disease, but it is difficult to directly assay these complex structures. This study sought to make this technology more amenable for study by obtaining epithelial cells from induced pluripotent stem cell-derived human intestinal organoids and incorporating them into small microengineered Chips. We then investigated if these cells within the Chip were polarized, had the 4 major intestinal epithelial subtypes, and were biologically responsive to exogenous stimuli...
2018: Cellular and Molecular Gastroenterology and Hepatology
Stefania Senger, Laura Ingano, Rachel Freire, Antony Anselmo, Weishu Zhu, Ruslan Sadreyev, William Allan Walker, Alessio Fasano
Background & Aims: Untreated necrotizing enterocolitis (NEC) can lead to massive inflammation resulting in intestinal necrosis with a high mortality rate in preterm infants. Limited access to human samples and relevant experimental models have hampered progress in NEC pathogenesis. Earlier evidence has suggested that bacterial colonization of an immature and developing intestine can lead to an abnormally high inflammatory response to bacterial bioproducts. The aim of our study was to use human fetal organoids to gain insights into NEC pathogenesis...
2018: Cellular and Molecular Gastroenterology and Hepatology
Ge-Ah Kim, Nicholas J Ginga, Shuichi Takayama
The gastrointestinal (GI) tract regulates physiologic responses in complex ways beyond facilitating nutrient entry into the circulatory system. Because of the anatomic location of the GI tract, studying in vivo physiology of the human gut, including host cell interaction with the microbiota, is limited. GI organoids derived from human stem cells are gaining interest as they recapitulate in vivo cellular phenotypes and functions. An underdeveloped capability that would further enhance the utility of these miniature models of the GI tract is to use sensors to quantitatively characterize the organoid systems with high spatiotemporal resolution...
2018: Cellular and Molecular Gastroenterology and Hepatology
Yuebang Yin, Sunrui Chen, Mohamad S Hakim, Wenshi Wang, Lei Xu, Wen Dang, Changbo Qu, Auke P Verhaar, Junhong Su, Gwenny M Fuhler, Maikel P Peppelenbosch, Qiuwei Pan
Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients and might play a role in the pathogenesis of inflammatory bowel disease (IBD). 6-Thioguanine (6-TG) has been widely used as an immunosuppressive drug for organ recipients and treatment of IBD in the clinic. This study aims to investigate the effects and mode-of-action of 6-TG on rotavirus replication. Human intestinal Caco2 cell line, 3D model of human primary intestinal organoids, laboratory rotavirus strain (SA11) and patient-derived rotavirus isolates were used...
August 2018: Antiviral Research
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